STAT3 dictates β-cell apoptosis by modulating PTEN in streptozocin-induced hyperglycemia
Qinjie Weng1,2, Mengting Zhao1, Jiahuan Zheng1
1Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, 310058, Hangzhou, China.
Abstract:
Insufficient pancreatic β-cell mass or insulin-producing β-cells are implicated in all forms of diabetes mellitus. However, the molecular mechanisms underlying β-cell destruction are complex and not fully defined. Here we observed that activation of STAT3 is intensely and specifically inhibited in β-cells under hyperglycemic conditions. By knocking out STAT3 specifically in mouse β-cells, we found that the loss of STAT3 sensitized mice to three low doses of STZ stimulation resulting in hyperglycemia. Mechanistically, accumulating PTEN, induced by STAT3 deficiency, directly represses phosphorylation of AKT, which negatively modulates transcription factor activation, dysregulates β-cell function, positively promotes apoptotic signaling, and finally induces β-cell apoptosis. Notably, the defective secretion of insulin and β-cells apoptosis was completely rescued by PTEN ablation in STAT3-null islets or PTEN inhibitor bpv(phen) treatment. Thus our data suggest that STAT3 is a vital modulator of β-cell survival and function, highlighting a critical role for STAT3 in the negative regulation of PTEN-AKT signaling pathway associated with β-cell dysfunction and apoptosis.
Insights
Signal transducer and activator of transcription 3 (STAT3) is crucial for pancreatic beta-cell survival. Loss of STAT3 in beta-cells leads to apoptosis and diabetes, mediated by PTEN/AKT pathway dysregulation.
Area of Science:
- Endocrinology
- Molecular Biology
- Diabetes Research
Background:
- Diabetes mellitus is linked to insufficient pancreatic beta-cell mass.
- The molecular mechanisms of beta-cell destruction are complex and not fully understood.
- STAT3 activation is inhibited in beta-cells under hyperglycemia.
Purpose of the Study:
- To investigate the role of STAT3 in beta-cell survival and function.
- To elucidate the molecular mechanisms by which STAT3 deficiency impacts beta-cells.
- To identify potential therapeutic targets for diabetes-related beta-cell dysfunction.
Main Methods:
- STAT3 knockout specifically in mouse beta-cells.
- Streptozotocin (STZ) induced hyperglycemia model.
- Analysis of PTEN and AKT signaling pathways.
- Assessment of insulin secretion and beta-cell apoptosis.
Main Results:
- STAT3 deficiency in beta-cells sensitized mice to STZ, leading to hyperglycemia.
- STAT3 deficiency caused PTEN accumulation, inhibiting AKT phosphorylation.
- This inhibition dysregulated beta-cell function and promoted apoptosis.
- PTEN ablation or inhibition rescued insulin secretion and prevented apoptosis.
Conclusions:
- STAT3 is a critical regulator of beta-cell survival and function.
- STAT3 negatively regulates the PTEN-AKT signaling pathway.
- Targeting STAT3 or the PTEN-AKT pathway may offer therapeutic strategies for diabetes.
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